One contribution toward the goal preventing cancer progression would be to identify environmental factors such as nutrients that may contribute to cancer survivorship. The optimal vitamin nutriture of cancer patients is not well established, and the role of vitamins in preventing the recurrence of clinically overt cancer has not been widely evaluated. Our preliminary data provide evidence that rapid depletion of the vitamin folic acid is associated with increased resistance of cultured human lung cancer and ovarian cells to the chemotherapeutic agent cisplatin. The overall goal of this project is to examine the hypothesis that folic acid influences the resistance in lung cancer cells to the action of cisplatin. We hypothesize, based on our preliminary data, that folate will prevent intrinsic and acquired resistance to cisplatin. To test this hypothesis, we propose the following two specific aims: Specific Aim 1: To determine whether altered folic acid concentrations can prevent or reverse resistance to the chemotherapeutic agent cisplatin. Specific Aim 2: To evaluate the mechanisms by which folic acid alters resistance to cisplatin. In the first specific aim, we will evaluate whether supplementation with folic acid decreases the resistance to cisplatin. We will test folate and cisplatin in several lung cancer cell lines. In Specific Aim 2, we will attempt to determine the mechanism by which folate supplementation decreases resistance by evaluating the effect of folate supplementation on levels of metabolites commonly associated with the development of resistance, and on expression of genes associated with development of resistance. If our studies are successful, a rationale for clinical trials aimed at evaluating the influence of vitamin status on resistance to chemotherapy in cancer patients would be established. If vitamin supplementation is ultimately found to decrease resistance to chemotherapeutic agents, then a simple and inexpensive approach to prevent, at least in part, the resistance that limits the effectiveness of chemotherapy will be realized.